ORGANIC LETTERS
Selective Synthesis of Phosphate Monoesters by Dehydrative Condensation of Phosphoric Acid and Alcohols Promoted by Nucleophilic Bases
2005 Vol. 7, No. 10 1999-2002
Akira Sakakura, Mikimoto Katsukawa, and Kazuaki Ishihara* Graduate School of Engineering, Nagoya UniVersity, Chikusa, Nagoya, 464-8603 Japan
[email protected] Received March 5, 2005
ABSTRACT
Phosphate monoesters are synthesized from a mixture of phosphoric acid (1 or 2 equiv) and alcohols (1 equiv) in the presence of tributylamine. The reaction is promoted by nucleophilic bases such as N-alkylimidazole and 4-(N,N-dialkylamino)pyridine. 2′,3′-O-Isopropylidene ribonucleosides are selectively converted to their 5′-monophosphates without the protection of amino groups in nucleobases.
Phosphate monoesters are some of the most important substances in medicinal chemistry, materials chemistry, and so on. Many methods for preparing phosphate monoesters have been reported.1 Phosphoryl chloride (POCl3) is one of the most widely used phosphorylating agents for alcohols. The reaction of alcohols with phosphoryl chloride in the presence of water and pyridine provides phosphate monoesters along with pyridine hydrochloride as a byproduct (Scheme 1, eq 1). Since phosphoryl chloride is very reactive, phosphate diesters and triesters are produced as byproducts when alcohols are reacted with an equimolar amount of phosphoryl chloride. Therefore, an excess amount of phosphoryl chloride is required for the selective synthesis of phosphate monoesters. From the perspective of green chemistry, the reaction of equimolar amounts of alcohols and phosphoric acid (H3PO4) is more attractive for the synthesis (1) For reviews, see: (a) Hayakawa, Y. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Winterfeldt, E., Eds.; Pergamon: Oxford, 1991; Vol. 6, pp 601-630. (b) Slotin, L. A. Synthesis 1976, 737. 10.1021/ol0504796 CCC: $30.25 Published on Web 04/20/2005
© 2005 American Chemical Society
Scheme 1.
Synthesis of Phosphate Monoesters
of phosphate monoesters, since the reaction produces only water as a byproduct (Scheme 1, eq 2). About 40 years ago, Honjo et al. reported the synthesis of 2′,3′-O-isopropylidene ribonucleoside 5′-monophosphates from the corresponding ribonucleosides and 5 equivalents of phosphoric acid in the presence of 10 equivalents of tributylamine (Bu3N) under reflux condition in dimethylformamide (DMF, 153 °C).2,3 In this pioneering work, an
excess amount of phosphoric acid was used and the reaction temperature was very high. Therefore, we investigated a method for synthesizing phosphate monoesters by the direct condensation of equimolar amounts of phosphoric acid and alcohols. We first investigated the reaction of equimolar amounts of 4-phenyl-1-butanol (1) and phosphoric acid in the presence of Bu3N (1 equiv) in various solvents (Table 1). Reactions
Table 1. Optimization of the Solvents in the Reaction of 1 with H3PO4a
entry
solvent
bp (°C)
1 2 3 4 5 6 7 8 9
DMF EtNO2 MeNO2 i-PrCN EtCN o-xylene DMF-EtNO2 (1:1) DMF-EtNO2 (1:3) DMF-o-xylene (1:1)
153 114 101 107 97 144
conv
(%)b
70 21 1 0 0 9 58 40 20
a
Reactions were carried out with 2 mmol of 1, H3PO4 and Bu3N in 4 mL of solvents at azeotropic reflux with the removal of water using MS 3A for 6 h. b Determined by RP-HPLC and 1H NMR.
were conducted for 6 h under azeotropic reflux with the removal of water (molecular sieves 3A in a Soxhlet thimble). Based on the solubility of phosphoric acid, aprotic polar solvents such as amides, nitroalkanes, and nitriles were thought to be suitable for the reaction.2 DMF provided phosphate monoester 2 in 70% yield (entry 1). When the reaction was carried out in nitroethane (bp 114 °C), 2 was obtained in 21% yield (entry 2). Nitromethane (bp 101 °C), isobutyronitrile (bp 107 °C), and propionitrile (bp 97 °C) provided 2 in
